CD94 is a C-type lectin expressed by natural killer (NK) cells and a subset of T cells. Blocking studies using anti-CD94 mAbs have suggested that it is a receptor for human leukocyte antigen class I molecules. We showed that NKG2A, a 43-kD protein, is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A is dependent on the association with CD94 as glycosylation patterns characteristic of mature proteins are found only in NKG2A that is associated with CD94. Analysis of NK cell clones showed that NKG2A was expressed in all NK cell clones whose CD16-dependent killing was inhibited by cross-linking CD94. The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A. Similar motifs are found on Ly49 and killer cell inhibitory receptors, which also transmit negative signals to NK cells. Recent evidence increasingly supports the active role of integrins and their extracellular matrix ligands in lymphoid cell development, activation and proliferation. Two strains for murine dystrophia muscularis whose genetic defect has been mapped to laminin-2, a ligand of integrin alpha6beta1, have provided a natural "knockout" and an excellent control in which to study the role of ECM and integrins in lymphoid development. The strain whose laminin-2 expression was "knocked out" was found to have altered thymocyte development. The other strain whose defect is a defined deletion in one component of laminin-2 displays comparable disease symptoms but normal thymocyte development. Integrin alpha6beta1 is implicated in this pathway in thymocyte development since its laminin-2 binding site is intact in the unaffected mouse strain. The (1 integrin has been knocked out through traditional means by two research groups and in each case has been shown to be embryonic lethal. We have cloned an appropriate (1 genomic fragment and engineered it for tissue-specific (thymus) knockout production. By deleting the (1 gene only from thymocytes, we expect to be able to study its impact on the in vivo development of the immune system.